A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction-Mediated Cancer Therapy.

Subcellular organelle-targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. Herein, a multichannel calcium ion (Ca2+ ) nanomodulator (CaNMCUR+CDDP ), i.e., a cisplatin (CDDP) and curcumin (CUR) co-incorporating calcium carbonate (CaCO3 ) nanoparticle, is prepared by a facile one-pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+ -overload-induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEG CaNMCUR+CDDP ) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria-targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging-guided organelle-targeted cancer therapy in the future.